1 substituted oxindoles and azaoxindoles

ABSTRACT

Compounds of Formula I have been shown to enhance the release of the neurotransmitter acetylcholine, and thus may be useful as chemical intermediates and as pharmacological agents in the treatment of diseases of man, such as in Alzheimer&#39;s Disease and other conditions involving learning and cognition, where subnormal levels of this neurochemical are found. ##STR1##

This is a division of application Ser. No. 08/392,017, filed Feb. 21,1995, now U. S. Pat. No. 5,519,132, which is a division of applicationSer. No. 08/191,416, filed Feb. 11, 1994, now U. S. Pat. No. 5,428,035,which is a division of application Ser. No. 07/957,152, filed Oct. 7,1992, now U. S. Pat. No. 5,296,478.

FIELD OF THE INVENTION

This invention relates to 1-substituted oxindole and azaoxindoles, topharmaceutical compositions thereof, and methods of use in mammals totreat cognitive disorders, neurological dysfunction, and/or mooddisturbances such as, but not limited to degenerative nervous systemdiseases. Additionally, these compounds can be used as reagents instudies on the biochemical mechanism of neurotransmitter diseases.

BACKGROUND OF THE INVENTION

Increasingly there is a need for effective treatments for nervoussystems disorders and neurological deficiencies. Many of these diseasescorrelate with increasing age due mainly to degenerative changes in thenervous system. Although in early stages of some diseases, certainsystems are rather specifically affected (e.g., cholinergic systems inAlzheimer's Disease and Myasthenia Gravis, the dopaminergic system inParkinson's Disease, etc.) multiple neurotransmitter systemsdeficiencies (acetylcholine, dopamine, norepinephrine, serotonin) aregenerally found at later stages of diseases such as senile dementia,multi-infarct dementia, Huntington's Disease, mental retardation, etc.This explains the generally observed multiple symptomology that includescognitive, neurological and effective/psychotic components (seeGottfries, Psychopharmacol., 86, 245 (1985)). Deficits in the synthesisand release of acetylcholine in the brain are generally thought to berelated to cognitive impairment (see Francis, et al., New England J.Med., 1, 313 (1985)) whereas neurological deficits (e.g. Parkinsoniansymptoms) and mood/mental changes may be related to impairment ofdopaminergic and serotonergic systems, respectively. Other neurologicaldeficits (e.g., Myasthenia Gravis) are related to cholinergicdeficiencies in the peripheral nervous system.

Treatment strategies employed previously encompass vasoactive drugs likevincamine and pentoxifylline; metabolic enhancers like ergoloidmesylates, piracetam, and naftidrofuryl; neurotransmitter precursorslike L-DOPA, choline, 5-hydroxytryptamine; transmitter metabolizingenzyme inhibitors such as physostigmine; neuropeptides likeadrenocorticotropic hormone and vasopressin-related peptides. Except forL-DOPA treatment for Parkinson's Disease and cholinesterase inhibitortreatment for Myasthenia Gravis, these treatment strategies havegenerally failed to enhance the residual function of the affectedsystems by enhancing the stimulus-induced release of neurotransmitters.Theoretically, such an enhancement would improve the signal-to-noiseratio during chemical transmission for information, thereby reducingdeficits in processes related to cognition, neurological function andmood regulation.

European Patent Application 311,010 discloses α,α-disubstitutedaromatics or heteroaromatics of the formula: ##STR2## or a salt thereof,which are useful as cognition enhancers.

U.S. Pat. No. 4,760,083 to Myers, et al. discloses that indolinones ofthe following formula are useful for treatment of cognitivedeficiencies: ##STR3## These references teach the necessity of twoheteroaryl groups for activity.

European Patent Application No. 0 415 102 A1 by Effland, et al.describes an invention related to the formula: ##STR4##

U.S. Pat. No. 3,595,866 to D. E. Butler describes an invention of theformula: ##STR5##

European Patent Application No. 0 347 698 A1 wherein Ting, et al.describes a compound of formula: ##STR6##

SUMMARY OF THE INVENTION

Presently it has been found that certain oxindoles and azaoxindoleshaving geminal substitutions enhance the stimulus-induced release ofneurotransmitters, specifically acetylcholine in nervous tissue, andthus improve processes involved in learning and memorization of anavoidance task.

According to the present invention, there are provided compounds of theformula ##STR7## and pharmaceutically acceptable salts thereof, wherein:

Q¹, Q² are each independently selected from the group:

(a) 4, 3, or 2-pyridyl,

(b) 2, 4, or 5-pyrimidyl,

(c) 2-pyrazinyl,

(d) 2-fluoro-4-pyridyl,

(e) aryl unsubstituted or substituted with 1-3 R²,

(f) 3- or 4-pyridazinyl

(g) 2- or 3-tetrahydrofuranyl

(h) 3- or 4-pyrozolyl

(i) (CH₂)p-Y, and

(j) OCOR¹ ;

A is CH or N;

T is selected from the group: N(Ph)₂, N(Me)₂, N(Ph) (Me), ##STR8##

Y is selected from the group:

H, OH, NHCOR¹, NHCO₂ ^(R) ¹, NHS(O)₂ R¹, F, Cl, Br, OR¹, S(O)_(r) R¹,CO₂ H, CO₂ R¹, OCOR¹, CN, CONR¹ R¹, CONHR¹, CONH₂, COR¹, CH═CHCO₂ R¹,aryl unsubstituted or substituted with 1-3 R², CCCO₂ R¹, CH═CHR¹, orCCR¹ ;

R¹ is independently selected at each occurrence from the group:

H, C₁ -C₄ alkyl, C₃ -C₇ cycloalkyl, C₄ -C₈ cycloalkylalkyl, arylsubstituted with 1-3 R², and alkaryl substituted with 1-3 R² ;

R² is F, Cl, Br, R³, OR³, NO₂, NH₂, NHR³, NR³ R³, CN, S (0)_(r) R³ ;

R³ is independently selected at each occurrence from the group: C₁ -C₄alkyl and phenyl;

m and n are independently 0-1;

p is 1-3;

r is 0-2; and

s is 0-3;

provided that when A is CH and the sum of m+n=1, then T cannot equalN(Ph)₂, N(Me)₂ or N(Ph) (Me).

PREFERRED EMBODIMENTS

Preferred compounds of this invention are those compounds of Formula Iwherein:

Q¹ and Q² are independently selected from the group:

(a) 4-pyridyl,

(b) 4-pyrimidyl,

(c) 2-fluoro-4-pyridyl,

(d) (CH₂) p-Y, and

(e) OCOR¹ ;

A is CH or N;

T is selected from the group: N(Ph)₂, N(Me)₂, N(Ph) (Me), ##STR9##

Y is selected from the group:

CO₂ R¹, CN, CONHR¹, NHCOR¹ or OCOR¹ ;

R¹ is alkyl of 1 to 4 carbon atoms;

m and n are independently 0-1; and

s is 0-3;

provided that when A is CH and the sum of m+n=1, then T cannot equalN(Ph)₂, N(Me)₂, N(Ph) (Me).

More preferred compounds of this invention are those preferred compoundswherein:

T is selected from the group:

N(Ph)₂, N(Me)₂, N(Ph) (Me), ##STR10## wherein s is 1-3;

provided that when A is CH and the sum of m+n=1, then T cannot equalN(Ph)₂, N(Me)₂, or N(Ph) (Me) .

Specifically preferred compounds of Formula I are:

(a)1,3-dihydro-1-(4-morpholinyl)-3,3-bis(4-pyridinylmethyl)-2H-indol-2-one;

(b)1,3-dihydro-1-(1-piperidinyl)-3,3-bis(4-pyridinylmethyl)-2H-indol-2-one;

(c)1,3-dihydro-1-(dimethylamino)-3,3-bis(4-pyridinylmethyl)-2H-indol-2-one;

(d)1,3-dihydro-1-(methylamino)-1-(phenylamino)-3,3-bis(4-pyridinylmethyl)-2H-indol-2-one;

(e)1,3-dihydro-3,3-bis(2-fluoro-4-pyridinylmethyl)-1-(4-morpholinyl)-2H-indol-2-one;

(f)1,3-dihydro-1-(4-methyl-1-piperazinyl)-3,3-bis(4-pyridinylmethyl)-2H-indol-2-onedihydrochloride;

(g) 1,3-dihydro-3,3-bis(benzyl)-1-(4-morpholinyl)-2H-indol-2-one;

(h) 1,3-dihydro-3,3-bis(benzyl)-1-(methylamino)-1-(phenylamino)-2H-indol-2-one;

(i) 1,3-dihydro-3-phenyl-1-(1-piperidinyl)-3-(4-pyridinylmethyl)-2H-indol-2-one;

(j) 1,3-dihydro-2-oxo-1-(4-morpholinyl)-3-(4-pyridinylmethyl)-2H-indol-3-acetic acid, ethyl ester;

(k)1,3-dihydro-1-(4-morpholinyl)-3,3-bis(4-pyridinylmethyl)-2H-pyrrolo[2,3b]pyridin-2-one;

(l)1,3-dihydro-2-oxo-1-piperidinyl-3-(4-pyridinylmethyl)-2H-indol-3-aceticacid, ethyl ester;

(m)1,3-dihydro-1-(4-morpholinyl)-3-phenyl-3-sulfonylmethoxy-2H-pyrrolo[2,3b]pyridin-2-one;

(n) 1,3-dihydro-1-(4-morpholinyl)-3-phenyl-2H-pyrrolo[2,3b]pyridin-2-one.

In addition, this invention provides novel intermediates of formulae:##STR11## wherein Q¹, m, A and T have the same meanings and valuesdescribed above for the compound of Formula I and its embodiments. Theseintermediates are useful for the preparation of compounds of Formula I.

Specifically preferred compounds of Formula IV are:

(a) 2-Hydroxy-N-(4-morpholinyl)-2-(3-pyridinyl)-acetamide;

(b) 2-Hydroxy-N-(1-piperidinyl)-2-(3-pyridinyl)-acetamide;

(c) 2-Hydroxy-2-phenyl-2-(3-pyridinyl)-acetic acid;

(d) 2-Hydroxy-N-(4-morpholinyl)-2-phenyl-2-(3-pyridinyl)-acetamide;

Specifically preferred compounds of Formula V are:

(a) 1,3-dihydro-1-(4-morpholinyl )-2H-pyrrolo [2,3b ]pyridin-2-onehydrochloride;

(b) 1,3-dihydro-1-(1-piperidinyl )-2H-pyrrolo [2,3b ]pyridin-2-onehydrochloride;

(c)1,3-dihydro-1-(4-morpholinyl)-3-phenyl-3-sulfonylmethyl-2H-pyrrolo[2,3b]pyridin-2-one;

(d)1,3-dihydro-1-(4-morpholinyl)-3-phenyl-2H-pyrrolo[2,3b]pyridin-2-one;

(e)1,3-dihydro-1-(4-morpholinyl)-3-hydroxy-3-phenyl-2H-pyrrolo[2,3b]pyridin-2-one.

It should be recognized that the above-identified groups of compoundsare preferred embodiments of this invention, but that their descriptionherein is in no way intended to limit the overall scope of thisinvention.

This invention also provides pharmaceutical compositions comprising asuitable pharmaceutical carrier and an amount of one or more of theabovedescribed compounds effective to treat cognitive or neurologicaldysfunction. Still further, this invention relates to a method oftreating cognitive or neurological dysfunction in a mammal comprisingadministering to the mammal a therapeutically effective amount of one ormore of the above-described compounds.

DETAILED DESCRIPTION OF THE INVENTION

The compounds herein described may have asymmetric centers. All chiral,enantiomeric, diastereomeric, and racemic forms are included in thepresent invention. Thus, the compounds of Formula (I) may be provided inthe form of an individual stereoisomer, a non-racemic stereoisomermixture, or a racemic mixture.

Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention.

When any variable occurs more than one time in any constituent or inFormula (I), or any other formula herein, its definition on eachoccurrence is independent of its definition at every other occurrence.Also, combinations of substituents and/or variables are permissible onlyif such combinations result in stable compounds.

As used herein, "alkyl" is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. As used herein "alkoxy" represents analkyl group of indicated number of carbon atoms attached through anoxygen bridge; "cycloalkyl" is intended to include saturated ringgroups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl; and "biycloalkyl" is intended to includesaturated bicyclic ring groups such as [3.3.0]bicyclooctane,[4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin),[2.2.2]bicyclooctane, and so forth. "Alkenyl" is intended to includehydrocarbon chains of either a straight or branched configuration andone or more unsaturated carbon-carbon bonds which may occur in anystable point along the chain, such as ethenyl, propenyl, and the like;and "alkynyl" is intended to include hydrocarbon chains of either astraight or branched configuration and one or more triple carbon-carbonbonds which may occur in any stable point along the chain, such asethynyl, propynyl and the like. "Cycloalkyl-alkyl" is intended toinclude cycloalkyl attached to alkyl. "Halo" as used herein refers tofluoro, chloro, bromo, and iodo; and "counterion" is used to represent asmall, negatively charged species such as chloride, bromide, hydroxide,acetate, sulfate, and the like.

As used herein, "aryl" or "aromatic residue" is intended to mean phenylor naphthyl; "carbocyclic" is intended to mean any stable 5- to 7-membered monocyclic or bicyclic or 7- to 14- membered bicyclic ortricyclic carbon ring, any of which may be saturated, partiallyunsaturated, or aromatic, for example, indanyl or tetrahydronaphthyl(tetralin).

As used herein, the term "heterocycle" is intended to mean a stable 5-to 7- membered monocyclic or bicyclic or 7- to 10- membered bicyclicheterocyclic ring which is either saturated or unsaturated, and whichconsists of carbon atoms and from 1 to 3 heteroatoms selected from thegroup consisting of N, O and S and wherein the nitrogen and sulfurheteroatoms may optionally be oxidized, and the nitrogen may optionallybe quaternized, and including any bicyclic group in which any of theabove-defined heterocyclic rings is fused to a benzene ring. Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom which results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. Examples of such heterocyclesinclude, but are not limited to, pyridyl, pyrimidinyl, furanyl, thienyl,pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl,benzothiophenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl orbenzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl,2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, decahydroquinolinyl, pyrazinyl, quinazzoyl,phthalazinyl, naphthyridinyl or octahydroisoquinolinyl.

The term "substituted", as used herein, means that one or more hydrogenatom(s) on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.

By "stable compound" or "stable structure" is meant herein a compoundthat is sufficiently robust to survive isolation to a useful degree ofpurity from a reaction mixture, and formulation into an efficacioustherapeutic agent.

As used herein, the terms "pharmaceutically acceptable salts" and"pharmaceutically suitable salts" refer to derivatives of the disclosedcompounds that are modified by making acid or base salts. Examplesinclude, but are not limited to, mineral or organic acid salts of basicresidues such as amines; alkali or organic salts of acidic residues suchas carboxylic acids. Pharmaceutically acceptable salts of the compoundsof the invention can be prepared by reacting the free acid or base formsof these compounds with a stoichiometric amount of the appropriate baseor acid in water or in an organic solvent, or in a mixture of the two;generally, nonaqueous media like ether, ethyl acetate, ethanol,isopropanol, or acetonitrile are preferred. Lists of suitable salts arefound in Remington's Pharmaceutical Sciences, 17th ed., Mack PublishingCompany, Easton, Pa., 1985, p. 1418, the disclosure of which is herebyincorporated by reference.

As used herein, the term "therapeutically effective amount" means thatamount of a drug or pharmaceutical agent that will elicit the biologicalor medical response of a tissue, system, animal or human subject that isbeing sought by a clinician or researcher.

Synthesis

The compounds of the present invention may be prepared according to thefollowing schemes and examples, using appropriate materials and arefurther exemplified by the following specific examples. Those skilled inthe art will readily understand that known variations of the conditionsand processes of the following preparative procedures can be used toprepare those compounds.

Compounds of Formula I may be prepared according to the procedure shownin Scheme I. This procedure involves treating compounds of Formula II##STR12## with a strong base, in solution, to prepare the alkali metalsalt, preferably the sodium salt of the 2H-pyrrolo [2,3b]pyridin-2-oneor the 2H-indol-2-one, which alkali metal salt thus obtained is furtherreacted, without isolation, with a halo-alkylating compound having theformula G-(CH₂)n-Q¹ in a non-reactive solvent; wherein G is a halogen,preferably bromine or chlorine, and n and Q¹ are as defined underFormula I. Suitable non-reactive solvents are aromatic hydrocarbons,such as benzene, toluene or xylene; ethers such as dioxane,tetrahydrofuran, dibutyl ether, or glycol ethers having no freehydroxyls; tertiary amides, such as N,N-dimethylformamide; and mixturesof these. Preferred solvents are N,N-dimethylformamide, tetrahydrofuranand toluene. In some instances, phase-transfer catalysis conditions canbe used, employing any of the solvents described above in conjunctionwith a quaternary ammonium salt and water. The temperature and durationof the reaction are not critical, and may be varied over a wide rangefrom room temperature for 24 hours to 80° C., for 3 hours. Preferredconditions are room temperature, and a duration of 2-3 hours. Equivalentamounts of the reagents can be used, but it is preferable to use thehaloalkylating in a slight excess.

Compounds of Formula II may be prepared from compounds of formula V asshown in Scheme II. In this scheme, a compound of formula V is firstreacted with a compound of formula Q² -(CH₂)_(n) CHO in the presence ofa suitable amine base, e.g. triethylamine, followed by reduction withsodium borohydride (NaBH4) to afford a compound of Formula II. Thesereactions typically take place in a lower alkanol solvent, such asmethanol, at a temperature of 0°to 80° C. for 30 minutes to 6 hours.##STR13##

Compounds of Formula II can also be prepared by the method disclosed inScheme 3. This scheme shows a procedure for the preparation of compoundsof Formula II wherein A is N and Q² is as defined under Formula I. Usingthis procedure, compounds of Formula II are prepared by coupling of a2-hydroxy-2-(3-pyridyl) acetamide of Formula III with a 1,1-disubstituted hydrazine of formula H₂ N-T, such as 4-aminomorpholine,in the presence of a suitable coupling agent, eg.1,3-dicyclohexylcarbodiimide or 1-hydroxybenzotriazole in a non-reactivesolvent, such as N,N-dimethylformamide or dioxane, to give a compound ofFormula IV. Compounds of formula IV can then be converted to compoundsof formula II (wherein A is N) with either sulfuric acid,methanesulfonyl chloride or anhydride, in a chlorinated solvent and theproduct obtained, when deemed appropriate, reduced with sodium-amalgamin a lower alkanol solvent, i.e., methanol at 0° C. for 2 hours.##STR14##

The preparation of compounds of Formula II, wherein A is CH, m=0 and Q²is Ph was disclosed by Butler et al., J. Med. Chem. 16, 49-54 (1973)which is herein incorporated by reference.

Compounds of Formula III, where m=0 and Q¹ is H have been described byThill et al., J. Org. Chem., 33, 4376-4380 (1968) which is hereinincorported by reference. Other compounds of Formula III may also beprepared using the methods of Thill et al.

Compounds of formula V, such as1,3-dihydro-1-(4-morpholinyl)-2H-indol-2-one (formula V wherein A isCH), are prepared utilizing conditions described in Legrel et al., Tet.Lett., 27, 5609-5610 (1986) which is herein incorporated by reference.Other compounds of Formula V may also be prepared using the method ofLegrel et al.

To prepare compounds of formula I, wherein m=n and Q¹ =Q², the proceduredescribed above for Scheme I may be used. However, in those examplesdeemed appropriate, a slight excess over 2 equivalents of thehaloalkylating agent should be used.

EXAMPLES

Analytical data were recorded for the compounds described below usingthe following general procedures. Proton NMR spectra were recorded on aVarian FT-NMR spectrometer (200 MHz or 300 MHz); chemical shifts wererecorded in ppm (∂) from an internal tetramethylsilane standard indeuterochloroform or deuterodimethylsulfoxide and coupling constants (J)are reported in Hz. Mass spectra (MS) or high resolution mass spectra(HRMS) were recorded on Finnegan MAT 8230 spectrometer or HewlettPackard 5988A model spectrometer. Melting points are uncorrected.Boiling points are uncorrected.

Reagents were purchased from commercial sources and, where necessary,purified prior to use according to the general procedures outlined by D.D. Perrin and W. L. F. Armarego, Purification of Laboratory Chemicals,3rd ed., (New York: Pergamon Press, 1988). Chromatography was performedon silica gel using the solvent systems indicated below. For mixedsolvent systems, the volume ratios are given. Parts and percentages areby weight unless otherwise specified. Common abbreviations include: THF(tetrahydrofuran), TBDMS (t-butyl-dimethylsilyl), DMF(dimethylformamide), Hz (hertz) TLC (thin layer chromatography). Alltemperatures are given in degrees centigrade (°C.).

The following examples and preparations are for illustrative purposesonly and are not to be construed as limiting the invention.

Example 1 ##STR15## 1,3-dihydro-1-(4-morpholinyl)-3,3-bis(4-pyridinylmethyl)-2H-indol-2-one

A mixture of 1,3-dihydro-1-(4-morpholinyl)-2H-indol-2-one (0.5g, 2.3mmole), 4-picolyl chloride hydrochloride (0.83 g, 5.0 mmole),benzyltriethylammonium chloride (0.053 g, 0.23 mmole) in toluene (5 ml)and 50% sodium hydroxide solution (3.6 ml) were heated at 70° C. forthree hours. The reaction was cooled to room temperature and poured intowater/chloroform (30 ml each). The layers were separated and the aqueouslayer extracted with additional chloroform (3×20 ml). The combinedorganic layers were washed with water (50 ml), brine (50 ml), dried overmagnesium sulfate, filtered and concentrated on a rotary evaporator. Theresidue was chromatographed on silica gel using methanol/chloroform(7%), and recrystallized from chloroform/hexane to afford 0.81 g (88%)of the desired product as a solid, m.p. 200°-203° C.; IR (KBr): 1711cm⁻¹ ; ¹ H NMR (CDCl₃, TMS) : δ8.26 (dd, J=4.4, 1.5 Hz, 2H), 7.37 (m,1H), dd, J=7.7, 1.4 Hz, 2H), 6.80 (dd, J=4.4, 1.5 Hz, 4H), 6.61 (dd,J=7.7, 1.1 Hz, 1H), 3.77 (dd, J=5.5, 1.1 Hz, 2H), 3.59 (m, 2H), 3.43(dd, J=11.4 Hz, 1.5 Hz, 2H), 3.37 (d, J=12.8 Hz, 2H), 3.14 (d, J=12.8Hz,2H), 2.01 (br.d, J=10.2 Hz, 2H); mass spec. m/e 401 (M+H, 100%);Anal. (C₂₄ H₂₄ N₄ O₂): C,H,N.

Example 2 ##STR16## 1,3-dihydro-1-(1-piperidinyl)-3,3-bis(4-pyridinylmethyl)-2H-indo-2-one

By substituting 1,3-dihydro-1-(1-piperidinyl)-2H-indol-2-one in Example1, the desired product was obtained; m.p. 140°-143° C. Anal. (C₂₅ H₂₆ N₄O): C,H,N.

Example 3 ##STR17## 1,3-dihydro-1-(dimethylamino)-3,3-bis(4-pyridinylmethyl)-2H-indol-2-one

By substituting 1,3-dihydro-1-(dimethylamino)-2H-indol-2-one in Example1, the desired product was obtained; m.p. 190°-193° C. Anal. (C₂₂ H₂₂ N₄O.0.25H₂ O): C,H,N.

Example 4 ##STR18## 1,3-dihydro-1-(diphenylamino)-3,3-bis(4-pyridinylmethyl)-2H-indol-2-one

By substituting 1,3-dihydro-1-(diphenylamino)-2H-indol-2-one in Example1, the desired product was obtained; m.p. 184°-186° C. Anal. (C₃₂ H₂₆ N₄O.0.5H₂ O): C,H,N.

Example 5 ##STR19##1,3-dihydro-1-(methylamino)-1-(phenylamino)-3,3-bis(4-pyridinylmethyl)-2H-indol-2-one

By substituting1,3-dihydro-1-(methylamino)-1-(phenylamino)-2H-indol-2-one in Example 1,the desired product was obtained; m.p. 184°-186° C. Anal. (C₃₂ H₂₆ N₄O.0.5H₂ O): C,H,N.

Example 6 ##STR20##1,3-dihydro-1-(4-methyl-1-piperazinyl)-3,3-bis(4-pyridinylmethyl)-2H-indol-2-onedihydrochloride

By substituting 1,3-dihydro-1-(4-methyl-1-piperazinyl)-2H-indol-2-one inExample 1, the desired product was obtained. The dihydrochloride saltwas prepared by treating the free base with anhydrous hydrogen chloridein ether to give a solid; m.p. 260° C. (dec). Anal. (C₂₅ H₂₇ N₅O..2HCl.H₂ O ): C,H,N,Cl.

Example 7 ##STR21## 1,3-dihydro-1-(4-morpholinyl)-3,3-bis(2-pyridinylmethyl)-2H-indol-2-one

By substituting 2-picolyl chloride hydrochloride in Example 1, thedesired product was obtained; m.p. 157°-159° C. Anal. (C₂₄ H₂₄ N₄ O₂):C,H,N.

Example 8 ##STR22##1,3-dihydro-3,3-bis(2-fluoro-4-pyridinylmethyl)-1-(4-morpholinyl)-2H-indol-2-one

Sodium hydride (60% oil dispension 92 mg, 2.3 mmole) was charged to aflame-dried flask and washed with pentane (3×3 ml). The flask wasflushed with nitrogen, tetrahydrofuran (10 ml) was added and the slurrywas stirred at 0° C. 1,3-dihydro-1-(4-morpholinyl)-2H-indol-2-one (225mg, 1.0 mmole) was added, the resulting solution was stirred for 15minutes at room temperature and recooled to 0° C. A solution of2-Fluoro-4-picolyl chloride (410 mg, 2.3 mmole) in tetrahydrofuran (10ml) was added and the solution allowed to stir at room temperatureovernight. The reaction was quenched into water (40 ml) and extractedwith dichloromethane(3×25 ml). The combined organics were washed withbrine, dried over magnesium sulfate, filter and concentrated underreduced pressure. The residue was chromatographed on silica gel ordirectly recrystallized from chloroform/hexane to give the desiredproduct; m.p. 198°-203° C. Anal. (C₂₄ H₂₂ F₂ N₄ O₂.0.25H₂ O): C,H,N,F.

Example 9 ##STR23##1,3-dihydro-1-(diphenylamino)-3,3-bis(2-fluoro-4-pyridinylmethyl)-2H-indol-2-one

By substituting 1,3-dihydro-1-(diphenylamino)-2H-indol-2-one in Example8, the desired product was obtained; m.p. 179°-180° C. Anal. (C₃₂ H₂₄ F₂N₄ O): C,H,N,F.

Example 10 ##STR24##1,3-dihydro-3,3-bis(benzyl)-1-(4-morpholinyl)-2H-indol-2-one

By substituting benzyl chloride in Example 8, the desired product wasobtained; m.p. 179°-180 C. (hexane). Anal. (C₂₆ H₂₆ N₂ O₂): C,H,N.

Example 11 ##STR25##1,3-dihydro-3,3-bis(benzyl)-1-(1-piperidinyl)-2H-indol-2-one

By substituting 1,3-dihydro-1-(1-piperidinyl)-2H-indol-2-one and benzylchloride in Example 8, the desired product was obtained; m.p. 94°-96 C.(hexane). Anal. (C₂₇ H₂₈ N₂ O): C,H,N.

Example 12 ##STR26##1,3-dihydro-3,3-bis(benzyl)-1-(methylamino)-1-(phenylamino)-2H-indol-2-one

By substituting1,3-dihydro-1-(methylamino)-1-(phenylamino)-2H-indol-2-one and benzylchloride in Example 8, the desired product was obtained; m.p. 171°-173C. (hexane). Anal. (C₂₉ H₂₆ N₂ O): C,H,N.

Example 13 ##STR27##1,3-dihydro-1-(4-morpholinyl)-3-phenyl-3-(4-pyridinylmethyl)-2H-indol-2-one

By substituting 1,3-dihydro-1-(4-morpholinyl)-3-phenyl-2H-indol-2-one inExample 1, the desired product was obtained; m.p. 190°-192.5° C. Anal.(C₂₄ H₂₃ N₃ O₂.0.25H₂ O): C,H,N.

Example 14 ##STR28##1,3-dihydro-3-phenyl-1-(1-piperidinyl)-3-(4-pyridinylmethyl)-2H-indol-2-one

By substituting 1,3-dihydro-3-phenyl-1-(1-piperidinyl)-2H-indol-2-one inExample 1, the desired product was obtained; m.p. 128°-131° C. Anal.(C₂₅ H₂₅ N₃ O): C,H,N.

Example 15 ##STR29##1,3-dihydro-3-(2-fluoro-4-pyridinylmethyl)-1-(4-morpholinyl)-3-phenyl-2H-indol-2-one

By substituting 1,3-dihydro-1-(4-morpholinyl)-3-phenyl-2H-indol-2-one inExample 8, the desired product was obtained; m.p. 170°-172° C.(hexane-ethyl acetate). Anal. (C₂₄ H₂₂ FN₃ O₂): C,H,N,F.

Example 16 ##STR30##1,3-dihydro-3-(2-fluoro-4-pyridinylmethyl)-3-phenyl-1-(1-piperidinyl)-2H,indol,-2-one

By substituting 1,3-dihydro-3-phenyl-1-(1-piperidinyl)-2H-indol-2-one inExample 8, the desired product was obtained; m.p. 129°-132° C. (hexane).Anal. (C₂₅ H₂₄ FN₃ O): C,H,N,F.

Example 17 ##STR31##1,3-dihydro-3-(2-fluoro-4-pyridinylmethyl)-1-(methylamino)-3-phenyl-1-(phenylamino)-2H-indol-2-one

By substituting1,3-dihydro-1-(methylamino)-3-phenyl-1-(phenylamino)-2H-indol-2-one inExample 8, the desired product was obtained; m.p. 186°-188° C. Anal.(C₂₇ H₂₂ FN₃ O): C,H,N,F.

Example 18 ##STR32##1,3-dihydro-3-(benzyl)-1-(4-morpholinyl)-3-phenyl-2H-indol-2-one

By substituting 1,3-dihydro-1-(4-morpholinyl)-3-phenyl-2H-indol-2-one inExample 8, the desired product was obtained; m.p. 159°-161° C.(hexane-ethyl acetate). Anal. (C₂₅ H₂₄ N₂ O₂): C,H,N.

Example 19 ##STR33##1,3-dihydro-3-(benzyl)-3-phenyl-1-(1-piperidinyl)-2H-indol-2-one

By substituting 1,3-dihydro-3-phenyl-1-(1-piperidinyl)-2H-indol-2-one inExample 8, the desired product was obtained; m.p. 114°-116° C.(cyclohexane). Anal. (C₂₆ H₂₆ N₂ O): C,H,N.

Example 20 ##STR34## 1,3-dihydro-1-(4-morpholinyl)-3-(4-pyridinylmethyl)-2H-indol-2-one

A mixture of 1,3-dihydro-1-(4-morpholinyl)-2H-indol-2-one (301 mg, 1.38mmole), triethylamine (0.22 ml, 1.52 mmole), 4-pyridinecarboxaldehyde(0.15 ml, 1.52 mmole) in methanol (3 ml) was refluxed for 30 minutes.The volatiles were evaporated and the crude product was partitionedbetween water and dichloromethane. The organic layer was washed withbrine, dried over magnesium sulfate, filtered and concentrated. Thecrude red oil was characterized by mass spec., m/e 308 (M+H, 100%) forthe aldol/dehydration product. The crude material was immediatelydissolved in methanol (10 ml), cooled to 0° C., to which was addedsodium borohydride (168 mg). After stirring 30 minutes, normalextractive workup afforded a yellow foam, which was purified by columnchromatography using 5% methanol-chloroform. The product wasrecrystallized from hexane-ethyl acetate to give 259 mg of a powder,m.p. 108°-110° C. Anal (C₁₈ H₁₉ N₃ O₂): C,H,N.

Example 21 ##STR35## 1,3-dihydro-2-oxo-1-(4-morpholinyl)-3-(4-pyridinylmethyl)-2H-indol-3-acetic acid; ethyl ester

The product obtained from Example 20 could be reacted with sodiumhydride and ethyl bromoacetate in a manner similar to Example 8 torender the product as a crystalline white solid, m.p. 168°-170° C.(hexanechloroform). High Res. Mass Spec. Calcd. for C₂₂ H₂₅ N₃ O₄ :396.1923 (M+H). Found: 396.1922.

Example 22 ##STR36##1,3-dihydro-3-hydroxy-1-(4-morpholinyl)-3-(4-pyridinylmethyl)-2H-indol-2-one

The product obtained from Example 20 could be reacted with sodiumhydride at room temperature in the absence of an inert atmosphere forthree hours. The reaction was poured into saturated ammoniumchloride/dichloromethane (30 ml each), the organic layer separated andwashed with brine. The organic were dried (MgSO₄), filtered,concentrated and purified on silica gel with 5% methanol in chloroform.The desired material was recrystallized with hexane-chloroform andobtained in 86% yield. m.p. 198°-200° C. High Res. Mass Spec. Calcd. forC₁₈ H₁₉ N₃ O₃ : 326.1505 (M+H). Found: 326.1508.

Example 23 ##STR37##1,3-dihydro-1-(piperidinyl)-3-(4-pyridinylmethyl)-2H-indol-2-one

In a manner analogous to that described in Example 20 and using1,3-dihydro-1-(1-piperidinyl)-2H-indol-2-one, the desired product wasobtained as a yellow amorphous solid, m.p. 83°-86° C. (hexane) in 53%overall yield. High Res. Mass Spec. Calcd. for C₁₉ H₂₁ N₃ O: 308.1763(M+H). Found: 308.1752

Example 24 ##STR38##1,3-dihydro-2-oxo-1-piperidinyl-3-(4-pyridinylmethyl)-2H-indol-3-aceticacid, ethyl ester

The product obtained from Example 23 could be reacted with sodiumhydride and ethyl bromoacetate in a manner similar to Example 8 torender the product as an oil. Mass Spec. Calcd. for C₂₂ H₂₅ N₃ O₄ : 394(M+H). Found: 394.

Example 25 ##STR39##1,3-dihydro-3-hydroxy-1-(1-piperidinyl)-3-(4-pyridinylmethyl)-2H-indol-2-one

1,3-dihydro-1-(1-piperidinyl)-3-(4-pyridinyl methyl)-2H-indol-2-onecould be reacted with sodium hydride and oxygen as reported in Example22. After column chromatography, the product was recrystallized fromhexane-chloroform to give the product as a brown solid, m.p. 156°-158°C. in 25% yield. High Res. Mass Spec. Calcd. for C₁₉ H₂₁ N₃ O₂ :324.1712 (M+H). Found: 324.1709.

Example 26 ##STR40##1,3-dihydro-3-hydroxy-1-(4-morpholinyl)-3-(2-pyridinylmethyl)-2H-indol-2-one

When the preparation of Example 7 is conducted with an insufficientamount of 2-picolyl chloride hydrochloride (25-50% deficiencies), thismaterial can be obtained in approximately 10% yield. This materialelutes from column chromatography at R_(f) =0.3 in 5% methanol inchloroform and was isolated as a solid, m.p. 168°-170° C. High Res. MassSpec. Calcd. for C₁₈ H₁₉ N₃ O₃ : 326.1505 (M+H). Found: 326.1503.

Example 27 ##STR41##1,3-dihydro-3-acetoxy-3-(2-pyridinylmethyl)-1-(4-morpholinyl)-2H-indol-2-one.

A mixture of alcohol from Example 26 (63 mg, 0.194 mmole)4-dimethylaminopyridine (78 mg, 0.639 mmole), acetic anhydride (0.06 ml,0. 639 mmole) in dichloromethane (10 ml) was stirred at 0° C. for 8hours. The volatiles were removed and the crude mixture applied directlyto a silica gel column and eluted with 5% methanol in chloroform (R_(f)=0.34). The product slowly crystallized from hexane-ethyl acetate at 0°C. to give 41 mg of colorless cubes, m.p. 107°-110° C. after filtration.IR (KBr): 1702 cm⁻¹. High Res. Mass Spec. Calcd. for C₂₀ H₂₁ N₃ O₄ :368.1610 (M+H). Found: 368. 1611.

Example 28 ##STR42##1,3-dihydro-3-acetoxy-1-(4-morpholinyl)-3-(4-pyridinylmethyl)-2H-indol-2-one,

By substituting1,3-dihydro-3-hydroxy-1-(4-morpholinyl)-3-(4-pyridinylmethyl)-2H-indol-2-onein Example 27, the desired product was obtained in 96% yield. Theproduct slowly crystallized from hexanechloroform to give a whitepowder, m.p. 178°-80° C. High Res. Mass Spec. Calcd. for C₂₀ H₂₁ N₃ O₄ :368.1610 (M+H). Found: 368.1608.

Example 29 ##STR43##1,3-dihydro-3-acetoxy-1-(1-piperidinyl)-3-(4-pyridinylmethyl)-2H-indol-2-one.

By substituting1,3-dihydro-3-hydroxy-1-(1-piperidinyl)-3-(4-pyridinylmethyl)-2H-indol-2-onein Example 27, the desired product was crystallized frompentane-dichloromethane to give a white powder, m.p. 139°-40° C. HighRes. Mass Spec. Calcd. for C₂₁ H₂₃ N₃ O₃ : 366.1818 (M+H). Found:366.1810.

Preparation 1 ##STR44## 2-(t-Butyldimethylsiloxy)-2-(3-pyridinyl)-aceticacid, methyl ester

A solution of 2-hydroxy-2-(3-pyridinyl)-acetic acid (31 g, 0.163 mole)in methanol (125 ml) and concentrated sulfuric acid (2 ml) was refluxedwith a modified Dean-Stark trap for 16 hours. The reaction was cooledand the methanol removed in vacuo. The solid was taken up in water (100ml), basified with potassium carbonate and extracted with chloroform.The organic layer was washed with brine, dried (MgSO₄), filtered andconcentrated in vacuo to give 20.94 g (77% yield) of the methyl ester asa yellow oil.

A solution of methyl ester (10 g, 5.98 mole), t-butyldimethylsilylchloride (10.82 g, 7.18 mole), and imidazole (10.87 g, 15.96 mole) inN,N-dimethylformamide (22 ml) was stirred under nitrogen at 35° C. for 5hours. The solution was taken up in chloroform (150 ml) and washedcopiously with water, dried over magnesium sulfate, filtered andconcentrated in vacuo to give 11.9 g of the title compound as a yellowoil in 92% yield. tlc (1:1 ethyl acetate/hexane) R_(f) =0.5. ¹ H NMR(CDCl₃, TMS): δ58.65 (d, J=2.2 Hz, 1H), 8.51 (dd, J=4.8, 1.5 Hz, 1H),7.76 (d, J=7.6 Hz, 1H), 7.24 (m, 1H), 5.22 (s, 1H), 3.66 (s, 3H), 0.86(s, 9H), 0.08 (s, 3H), 0.04 (s, 3H). MS (NH_(3/) CI) m/e 282.0 (M+H,100%). Anal (C₁₄ H₂₃ NO₃ Si): C,H,N,Si.

Preparation 2 ##STR45##2-Hydroxy-N-(4-morpholinyl)-2-(3-pyridinyl)-acetamide

To a 0° C. solution of 4-aminomorpholine (5.14 ml, 53.3 mmole) inchloroform (50 ml) under nitrogen was added trimethylaluminum (2Msolution in hexanes, 26.6 ml). The solution was stirred at roomtemperature for 1 hour. A solution of2-(t-butyldimethylsiloxy)-2-(3-pyridinyl) acetic acid, methyl ester (6.0g, 21.3 mmole) in chloroform (12 ml) was added dropwise and the stirringcontinued at 45° C. for 4 hours. The reaction was quenched intopotassium sodium tartrate (saturated, 150 ml) and stirred for 15minutes. Extraction with chloroform, followed by drying (MgSO₄),filtering and concentration gave a crude yellow oil which was purifiedby silica gel using 7% methanol in chloroform (R_(f) =0.33) to yield 4.4g (57% yield) of the silyl ether.

The silyl ether was deprotected under standard conditions, usingtetrabutylammonium fluoride (1M solution in THF) to give a crude oil,which was directly purified on silica gel using 10% methanol inchloroform. The desired product, 3.54 g, was obtained in 52% overallyield. Recrystallization from ethyl acetate/hexane afforded whitecrystals, m.p. 129-132 Anal. (C₁₁ H₁₅ N₃ O₃): C,H,N.

Preparation 3 ##STR46##2-Hydroxy-N-(1-piperidinyl)-2-(3-pyridinyl)-acetamide

By substituting 1-aminopiperidine in Preparations 1 and 2, the desiredproduct was obtained, m.p. 162-164 Anal. (C₁₂ H₁₆ N₃ O₂.0.2H₂ O): C,H,N.

Example 30 ##STR47##3-dihydro-1-(4-morpholinyl)-2H-pyrrolo[2,3b]pyridin-2-one hydrochloride

A solution of 2-hydroxy-N-(4-morpholinyl)-2-(3-pyridinyl) -acetamide(1.0 g, 4.2 mole) and triethylamine (1.3 ml, 9.3 mmole) was stirred inmethylene chloride (65 ml) and dioxane (11 ml) at 0° C. under nitrogen.Methanesulfonic anhydride (1.62 g, 9.3 mmol) in methylene chloride (20ml) was added and the reaction was allowed to warm to room temperatureafter 15 minutes. Additional triethylamine (9.3 mole) was added andfollowing one hour of stirring at 25° C., a third portion oftriethylamine (9.3 mmole) was added. After 2 hours of further stirringat room temperature, the solvent was removed in vacuo. The dark residuewas purified by column chromatography using silica gel and 7% methanolin chloroform. The desired product was obtained and the hydrochloridesalt was formed using anhydrous hydrogen chloride in ether (1M) andethyl acetate, m.p. 231-235 (dec). Anal (C₁₁ H₁₃ N₃ O₂.HCl): C,H,N,Cl.

Example 31 ##STR48##3-dihydro-1-(1-piperidinyl)-2H-pyrrolo[2,3b]pyridin-2-one hydrochloride

By substituting 2-hydroxy-N-(1-piperidinyl)-2-(3-pyridinyl)-acetamine inExample 30, the desired product was obtained. For characterizationpurposes, the HCl salt was prepared, m.p. 180-185 (dec). Anal. (C₁₂ H₁₅N₃ O.HCl): C,H,N,Cl.

Example 32 ##STR49## 1,3-dihydro-1-(4-morpholinyl)-3,3-bis(4-pyridinylmethyl)-2H-pyrrolo[2,3b]pyridin-2-one

By substituting1,3-dihydro-1-(4-morpholinyl)-2H-pyrrolo[2,3b]pyridin-2-one and atoluene (0° C.) solution of free-based 4-picolyl chloride hydrochloridein Example 8, the desired product was obtained after columnchromatography using 7% methanol in chloroform. m.p. 196°-198° C. HighRes. Mass Spec. Calcd. for C₂₃ H₂₃ N₅ O₂ : 402.1930 (M+H). Found:402.1940.

Preparation 4 ##STR50## 2-Hydroxy-2-phenyl-2-(3-pyridinyl)-acetic acid

To a -78° C. solution of 3-bromopyridine (9.6 ml, 0.10 mole) in ether(500 ml) was added n-butyllithium (2.5M in hexane, 40 ml). Afterstirring for 45 minutes at this temperature, the solution wastransferred via cannula to a -78° C. solution of methyl benzoylformate(14.2 ml, 0.10 mole) in ether (500 ml). After an additional 20 minutesat -78° C., the reaction was allowed to slowly warm to room temperaturefollowed by heating to reflux for 2 hours. The reaction was quench with1/2 saturated ammonium chloride (500 ml), the layers were separated andthe aqueous fraction extracted with ether. The combined extracts werewashed with brine, dried over magnesium sulfate, filtered , concentratedin vacuo (and the orange residue was heated to 75° C. at 1 mm for 4hours). Purification was carried out using silica gel and 7% methanol inchloroform to render 7.96 g of the hydroxyester.

The ester (7.9 g, 0.33 mole) was hydrolyzed in ethanol (34 ml), dioxane(67 ml) and water (13 ml), using potassium hydroxide (3.65 g, 0.065mole) at reflux for 2 hours. The volatiles were removed under vacuum at40° C. The resulting syrup was diluted with water (60 ml) and theneutral impurities extracted with dichloromethane. The pH of the aqueousphase was adjusted to 2.7 using concentrated hydrochloric acid andfollowing brief heating, the product precipitated as a solid, 5.73 g;m.p. 185°-187° C. Anal. (C₁₃ H₁₁ NO₃): C,H,N.

Preparation 5 ##STR51##2-Hydroxy-N-(4-morpholinyl)-2-phenyl-2-(3-pyridinyl)-acetamide

A mixture of 2-hydroxy-2-phenyl-2-(3-pyridinyl)acetic acid (3.48 g, 0.015 mole), 1-hyrdoxybenzotriazole hydrate (4.10 g, 0.03 mole),1,3-Dicyclohexycarbodiimide (3.09 g, 0.015 mole), 4-aminomorpholine(1.45 ml, 0.015 mole), sodium bicarbonate (1.26 g, 0.015 mole),N,N-dimethyformamide (36 ml) and dioxane (36 ml) were stirred at roomtemperature overnight. The volatiles were removed in vacuo,dichloromethane (170 ml) was added and following filtration, the organiclayer was washed with saturated sodium bicarbonate and brine. Afterdrying, filtration and concentration, the residue was purified by columnchromatography using 10% methanol in chloroform to give 3.92 g of theproduct as a white foam. High Res. Mass Spec. Calcd. for C₁₇ H₁₉ N₃ O₃ :314.1505 (M+H). Found: 314.1501.

Example 33 ##STR52##1,3-dihydro-1-(4-morpholinyl)-3-phenyl-3-sulfonylmethyl-2H-pyrrolo[2,3b]pyridin-2-one

By substituting2-hydroxy-N-(4-morpholinyl)-2-phenyl-2-(3-pyridinyl)-acetamide and usingmethane sulfonyl chloride in Preparation 3, the desired product wasobtained as an oil. ¹ H NMR (CDCl₃, TMS): d 8.38 (dd, J=5.5, 1.8 Hz,1H), 8.13 (dd, J=7.7,1.5 Hz, 1H), 7.97 (m, 2H), 7.46 (m, 3H), 7.12 (dd,J=7.3,1.5 Hz, 1h), 3.94 (t,J=4.4 Hz,4H), 3.58 (br.t, 4H), 3.00 (s,3H).¹³ C NMR (CDCl₃, ppm): 168.30, 156.10, 149.39, 135.45, 130.41, 129.80,129.41, 127.79, 119.38, 115.76, 74.27, 66.93, 51.28, 36.69. Mass spec.m/e 374 (M+H, 100%).

Example 34 ##STR53##1,3-dihydro-1-(4-morpholinyl)-3-phenyl-2H-pyrrolo[2,3b]pyridin-2-one

A solution of the product from Example 33 could be reduced usingsodium-amalgam in phosphate-buffered methanol to give the desiredproduct as an oil. Mass spec. m/e 296 (M+H, 100%)

Example 35 ##STR54##1,3-dihydro-1-(4-morpholinyl)-3-hydroxy-3-phenyl-2H-pyrrolo[2,3b]pyridin-2-one

A by-product was isolated in 10% yield from undesired chromatographyfractions from Example 33. IR (KBr): 3368, 1732 cm⁻¹. High Res. MassSpec. Calcd. for C₁₇ H₁₇ N₃ O₃ : 312.1348 (M+H). Found: 312.1350.

By using the methods illustrated in the above examples, compounds inTable I can be prepared.

                  TABLE I    ______________________________________    Ex   A      m     Q1     n   Q2        T    ______________________________________    36   CH     1     4-pyr  1   3-pyr     4-morpholinyl    37   CH     1     4-pyr  1   2-pyr     4-morpholinyl    38   CH     1     4-pyr  1   2-F-4-pyr 4-morpholinyl    39   CH     1     3-pyr  1   3-pyr     4-morpholinyl    40   CH     1     4-pym  1   4-pym     4-morpholinyl    41   CH     1     4-pym  1   4-pyr     4-morpholinyl    42   CH     1     4-pym  1   2-F-4-pyr 4-morpholinyl    43   CH     1     4-pyr  1   (CH.sub.2).sub.2 CO.sub.2 Et                                           4-morpholinyl    44   CH     1     4-pyr  1   CN        4-morpholinyl    45   CH     1     4-pyr  1   (CH.sub.2).sub.2 CN                                           4-morpholinyl    46   CH     1     4-pyr  1   CONH.sub.2                                           4-morpholinyl    47   CH     1     4-pyr  1   (CH.sub.2).sub.2 CONH.sub.2                                           4-morpholinyl    48   CH     1     4-pyr  1   Ph        4-morpholinyl    49   CH     1     4-pym  1   (CH.sub.2).sub.2 CO.sub.2 Et                                           4-morpholinyl    50   CH     1     4-pym  1   (CH.sub.2).sub.2 CN                                           4-morpholinyl    51   N      1     2-F-4-pyr                             1   2-F-4-pyr 4-morpholinyl    52   N      1     Ph     1   Ph        4-morpholinyl    53   N      1     4-pyr  1   CO.sub.2 Et                                           4-morpholinyl    54   N      1     4-pyr  1   3-pyr     4-morpholinyl    55   N      1     4-pyr  1   2-pyr     4-morpholinyl    56   N      1     4-pyr  1   2-F-4-pyr 4-morpholinyl    57   N      1     3-pyr  1   3-pyr     4-morpholinyl    58   N      1     4-pym  1   4-pym     4-morpholinyl    59   N      1     4-pym  1   4-pyr     4-morpholinyl    60   N      1     4-pym  1   2-F-4-pyr 4-morpholinyl    61   N      1     4-pyr  1   (CH.sub.2).sub.2 CO.sub.2 Et                                           4-morpholinyl    62   N      1     4-pyr  1   CN        4-morpholinyl    63   N      1     4-pyr  1   (CH.sub.2).sub.2 CN                                           4-morpholinyl    64   N      1     4-pyr  1   CONH.sub.2                                           4-morpholinyl    65   N      1     4-pyr  1   (CH.sub.2).sub.2 CONH.sub.2                                           4-morpholinyl    66   N      1     4-pyr  1   Ph        4-morpholinyl    67   N      1     4-pym  1   (CH.sub.2).sub.2 CO.sub.2 Et                                           4-morpholinyl    68   N      1     4-pym  1   (CH.sub.2).sub.2 CN                                           4-morpholinyl    69   CH     1     4-pyr  1   3-pyr     1-piperidinyl    70   CH     1     4-pyr  1   2-pyr     1-piperidinyl    71   CH     1     4-pyr  1   2-F-4-pyr 1-piperidinyl    72   CH     1     3-pyr  1   3-pyr     1-piperidinyl    73   CH     1     4-pym  1   4-pym     1-piperidinyl    74   CH     1     4-pym  1   4-pyr     1-piperidinyl    75   CH     1     4-pym  1   2-F-4-pyr 1-piperidinyl    76   CH     1     4-pyr  1   (CH.sub.2).sub.2 CO.sub.2 Et                                           1-piperidinyl    77   CH     1     4-pyr  1   CN        1-piperidinyl    78   CH     1     4-pyr  1   (CH.sub.2).sub.2 CN                                           1-piperidinyl    79   CH     1     4-pyr  1   CONH.sub.2                                           1-piperidinyl    80   CH     1     4-pyr  1   (CH.sub.2).sub.2 CONH.sub.2                                           1-piperidinyl    81   CH     1     4-pyr  1   Ph        1-piperidinyl    82   CH     1     4-pym  1   (CH.sub.2).sub.2 CO.sub.2 Et                                           1-piperidinyl    83   CH     1     4-pym  1   (CH.sub.2).sub.2 CN                                           1-piperidinyl    84   N      1     4-pyr  1   4-pyr     1-piperidinyl    85   N      1     Ph     1   Ph        1-piperidinyl    86   N      1     2-F-4-pyr                             1   2-F-4-pyr 1-piperidinyl    87   N      1     4-pyr  1   CO.sub.2 Et                                           1-piperidinyl    88   N      1     4-pyr  1   3-pyr     1-piperidinyl    89   N      1     4-pyr  1   2-pyr     1-piperidinyl    90   N      1     4-pyr  1   2-F-4-pyr 1-piperidinyl    91   N      1     3-pyr  1   3-pyr     1-piperidinyl    92   N      1     4-pym  1   4-pym     1-piperidinyl    93   N      1     4-pym  1   4-pyr     1-piperidinyl    94   N      1     4-pym  1   2-F-4-pyr 1-piperidinyl    95   N      1     4-pyr  1   (CH.sub.2).sub.2 CO.sub.2 Et                                           1-piperidinyl    96   N      1     4-pyr  1   CN        1-piperidinyl    97   N      1     4-pyr  1   (CH.sub.2).sub.2 CN                                           1-piperidinyl    98   N      1     4-pyr  1   CONH.sub.2                                           1-piperidinyl    99   N      1     4-pyr  1   (CH.sub.2).sub.2 CONH.sub.2                                           1-piperidinyl    100  N      1     4-pyr  1   Ph        1-piperidinyl    101  N      1     4-pym  1   (CH.sub.2).sub.2 CO.sub.2 Et                                           1-piperidinyl    102  N      1     4-pym  1   (CH.sub.2).sub.2 CN                                           1-piperidinyl    103  CH     1     Ph     1   Ph        4-Me-1-                                           piperazinyl    104  CH     1     4-pyr  1   3-pyr     4-Me-1-                                           piperazinyl    105  CH     1     4-pyr  1   2-pyr     4-Me-1-                                           piperazinyl    106  CH     1     4-pyr  1   2-F-4-pyr 4-Me-1-                                           piperazinyl    107  CH     1     3-pyr  1   3-pyr     4-Me-1-                                           piperazinyl    108  CH     1     4-pym  1   4-pym     4-Me-1-                                           piperazinyl    109  CH     1     4-pym  1   4-pyr     4-Me-1-                                           piperazinyl    110  CH     1     4-pym  1   2-F-4-pyr 4-Me-1-                                           piperazinyl    111  CH     1     4-pyr  1   (CH.sub.2).sub.2 CO.sub.2 Et                                           4-Me-1-                                           piperazinyl    112  CH     1     4-pyr  1   CN        4-Me-1-                                           piperazinyl    113  CH     1     4-pyr  1   (CH.sub.2).sub.2 CN                                           4-Me-1-                                           piperazinyl    114  CH     1     4-pyr  1   CONH.sub.2                                           4-Me-1-                                           piperazinyl    115  CH     1     4-pyr  1   (CH.sub.2).sub.2 CONH.sub.2                                           4-Me-1-                                           piperazinyl    116  CH     1     4-pyr  1   Ph        4-Me-1-                                           piperazinyl    117  CH     1     4-pym  1   (CH.sub.2).sub.2 CO.sub.2 Et                                           4-Me-1-                                           piperazinyl    118  CH     1     4-pym  1   (CH.sub.2).sub.2 CN                                           4-Me-1-                                           piperazinyl    119  N      1     4-pyr  1   4-pyr     4-Me-1-                                           piperazinyl    120  N      1     Ph     1   Ph        4-Me-1-                                           piperazinyl    121  N      1     2-F-4-pyr                             1   2-F-4-pyr 4-Me-1-                                           piperazinyl    122  N      1     4-pyr  1   CO.sub.2 Et                                           4-Me-1-                                           piperazinyl    123  N      1     4-pyr  1   3-pyr     4-Me-1-                                           piperazinyl    124  N      1     4-pyr  1   2-pyr     4-Me-1-                                           piperazinyl    125  N      1     4-pyr  1   2-F-4-pyr 4-Me-1-                                           piperazinyl    126  N      1     3-pyr  1   3-pyr     4-Me-1-                                           piperazinyl    127  N      1     4-pym  1   4-pym     4-Me-1-                                           piperazinyl    128  N      1     4-pym  1   4-pyr     4-Me-1-                                           piperazinyl    129  N      1     4-pym  1   2-F-4-pyr 4-Me-1-                                           piperazinyl    130  N      1     4-pyr  1   (CH.sub.2).sub.2 CO.sub.2 Et                                           4-Me-1-                                           piperazinyl    131  N      1     4-pyr  I   CN        4-Me-1-                                           piperazinyl    132  N      1     4-pyr  I   (CH.sub.2).sub.2 CN                                           4-Me-1-                                           piperazinyl    133  N      1     4-pyr  1   CONH.sub.2                                           4-Me-1-                                           piperazinyl    134  N      1     4-pyr  1   (CH.sub.2).sub.2 CONH.sub.2                                           4-Me-1-                                           piperazinyl    135  N      1     4-pyr  1   Ph        4-Me-1-                                           piperazinyl    136  N      1     4-pym  1   (CH.sub.2).sub.2 CO.sub.2 Et                                           4-Me-1-                                           piperazinyl    137  N      1     4-pym  1   (CH.sub.2).sub.2 CN                                           4-Me-1-                                           piperazinyl    138  CH     1     4-pyr  1   3-pyr     N(Ph)(Me)    139  CH     1     4-pyr  1   2-pyr     N(Ph)(Me)    140  CH     1     4-pyr  1   2-F-4-pyr N(Ph)(Me)    141  CH     1     3-pyr  1   3-pyr     N(Ph)(Me)    142  CH     1     4-pym  1   4-pym     N(Ph)(Me)    143  CH     1     4-pym  1   4-pyr     N(Ph)(Me)    144  CH     1     4-pym  1   2-F-4-pyr N(Ph)(Me)    145  CH     1     4-pyr  1   (CH.sub.2).sub.2 CO.sub.2 Et                                           N(Ph)(Me)    146  CH     1     4-pyr  1   CN        N(Ph)(Me)    147  CH     1     4-pyr  1   (CH.sub.2).sub.2 CN                                           N(Ph)(Me)    148  CH     1     4-pyr  1   CONH.sub.2                                           N(Ph)(Me)    149  CH     1     4-pyr  1   (CH.sub.2).sub.2 CONH.sub.2                                           N(Ph)(Me)    150  CH     1     4-pyr  1   Ph        N(Ph)(Me)    151  CH     1     4-pym  1   (CH.sub.2).sub.2 CO.sub.2 Et                                           N(Ph)(Me)    152  CH     1     4-pym  1   (CH.sub.2).sub.2 CN                                           N(Ph)(Me)    153  N      1     4-pyr  1   4-pyr     N(Ph)(Me)    154  N      1     Ph     1   Ph        N(Ph)(Me)    155  N      1     2-F-4-pyr                             1   2-F-4-pyr N(Ph)(Me)    156  N      1     4-pyr  1   CO.sub.2 Et                                           N(Ph)(Me)    157  N      1     4-pyr  1   3-pyr     N(Ph)(Me)    158  N      1     4-pyr  1   2-pyr     N(Ph)(Me)    159  N      1     4-pyr  1   2-F-4-pyr N(Ph)(Me)    160  N      1     3-pyr  1   3-pyr     N(Ph)(Me)    161  N      1     4-pym  1   4-pym     N(Ph)(Me)    162  N      1     4-pym  1   4-pyr     N(Ph)(Me)    163  N      1     4-pym  1   2-F-4-pyr N(Ph)(Me)    164  N      1     4-pyr  1   (CH.sub.2).sub.2 CO.sub.2 Et                                           N(Ph)(Me)    165  N      1     4-pyr  1   CN        N(Ph)(Me)    166  N      1     4-pyr  1   (CH.sub.2).sub.2 CN                                           N(Ph)(Me)    167  N      1     4-pyr  1   CONH.sub.2                                           N(Ph)(Me)    168  N      1     4-pyr  1   (CH.sub.2).sub.2 CONH.sub.2                                           N(Ph)(Me)    169  N      1     4-pyr  1   Ph        N (Ph)(Me)    170  N      1     4-pym  1   (CH.sub.2).sub.2 CO.sub.2 Et                                           N(Ph)(Me)    171  N      1     4-pym  1   (CH.sub.2).sub.2 CN                                           N(Ph)(Me)    172  CH     1     4-pyr  1   3-pyr     N(Ph)(Me)    173  CH     1     4-pyr  1   2-pyr     N(Me).sub.2    174  CH     1     4-pyr  1   2-F-4-pyr N(Me).sub.2    175  CH     1     3-pyr  1   3-pyr     N(Me).sub.2    176  CH     1     4-pym  1   4-pym     N(Me).sub.2    177  CH     1     4-pym  1   4-pyr     N(Me).sub.2    178  CH     1     4-pym  1   2-F-4-pyr N(Me).sub.2    179  CH     1     4-pyr  1   (CH.sub.2).sub.2 CO.sub.2 Et                                           N(Me).sub.2    180  CH     1     4-pyr  1   CN        N(Me).sub.2    181  CH     1     4-pyr  1   (CH.sub.2).sub.2 CN                                           N(Me).sub.2    182  CH     1     4-pyr  1   CONH.sub.2                                           N(Me).sub.2    183  CH     1     4-pyr  1   (CH.sub.2).sub.2 CONH.sub.2                                           N(Me).sub.2    184  CH     1     4-pyr  1   Ph        N(Me).sub.2    185  CH     1     4-pym  1   (CH.sub.2).sub.2 CO.sub.2 Et                                           N(Me).sub.2    186  CH     1     4-pym  1   (CH.sub.2).sub.2 CN                                           N(Me).sub.2    187  N      1     4-pyr  1   4-pyr     N(Me).sub.2    188  N      1     Ph     1   Ph        N(Me).sub.2    189  N      1     2-F-4-pyr                             1   2-F-4-pyr NMe.sub.2    190  N      1     4-pyr  1   CO.sub.2 Et                                           NMe.sub.2    191  N      1     4-pyr  1   3-pyr     NMe.sub.2    192  N      1     4-pyr  1   2-pyr     NMe.sub.2    193  N      1     4-pyr  1   2-F-4-pyr NMe.sub.2    194  N      1     3-pyr  1   3-pyr     NMe.sub.2    195  N      1     4-pym  1   4-pym     NMe.sub.2    196  N      1     4-pym  1   4-pyr     NMe.sub.2    197  N      1     4-pym  1   2-F-4-pyr NMe.sub.2    198  N      1     4-pyr  1   (CH.sub.2).sub.2 CO.sub.2 Et                                           NMe.sub.2    199  N      1     4-pyr  1   CN        NMe.sub.2    200  N      1     4-pyr  1   (CH.sub.2).sub.2 CN                                           NMe.sub.2    201  N      1     4-pyr  1   CONH.sub.2                                           NMe.sub.2    202  N      1     4-pyr  1   (CH.sub.2).sub.2 CONH.sub.2                                           NMe.sub.2    203  N      1     4-pyr  1   Ph        NMe.sub.2    204  N      1     4-pym  1   (CH.sub.2).sub.2 CO.sub.2 Et                                           NMe.sub.2    205  N      1     4-pym  1   (CH.sub.2).sub.2 CN                                           NMe.sub.2    206  N      1     2-F-4-pyr                             1   2-F-4-pyr NPh.sub.2    207  N      1     4-pyr  1   CO.sub.2 Et                                           NPh.sub.2    208  N      1     4-pyr  1   3-pyr     NPh.sub.2    209  N      1     4-pyr  1   2-pyr     NPh.sub.2    210  N      1     4-pyr  1   2-F-4-pyr NPh.sub.2    211  N      1     3-pyr  1   3-pyr     NPh.sub.2    212  N      1     4-pym  1   4-pym     NPh.sub.2    213  N      1     4-pym  1   4-pyr     NPh.sub.2    214  N      1     4-pym  1   2-F-4-pyr NPh.sub.2    215  N      1     4-pyr  1   (CH.sub.2).sub.2 CO.sub.2 Et                                           NPh.sub.2    216  N      1     4-pyr  1   CN        NPh.sub.2    217  N      1     4-pyr  1   (CH.sub.2).sub.2 CN                                           NPh.sub.2    218  N      1     4-pyr  1   CONH.sub.2                                           NPh.sub.2    219  N      1     4-pyr  1   (CH.sub.2).sub.2 CONH.sub.2                                           NPh.sub.2    220  N      1     4-pyr  1   Ph        NPh.sub.2    221  N      1     4-pym  1   (CH.sub.2).sub.2 CO.sub.2 Et                                           NPh.sub.2    222  N      1     4-pym  1   (CH.sub.2).sub.2 CN                                           NPh.sub.2    223  N      0     Ph     1   4-pyr     4-morpholinyl    224  N      0     Ph     1   2-F-4-pyr 4-morpholinyl    225  N      0     Ph     1   4-pym     4-morpholinyl    226  N      0     Ph     1   Ph        4-morpholinyl    227  N      0     Ph     0   OCOCH.sub.3                                           4-morpholinyl    228  N      0     Ph     1   4-pyr     1-piperidinyl    229  N      0     Ph     1   2-F-4-pyr 1-piperidinyl    230  N      0     Ph     1   4-pym     1-piperidinyl    231  N      0     Ph     1   Ph        1-piperidinyl    232  N      0     Ph     0   OCOCH.sub.3                                           1-piperidinyl    233  N      0     Ph     1   4-pyr     4-Me-1-                                           piperazinyl    234  N      0     Ph     1   2-F-4-pyr 4-Me-1-                                           piperazinyl    235  N      0     Ph     1   4-pym     4-Me-1-                                           piperazinyl    236  N      0     Ph     1   Ph        4-Me-1-                                           piperazinyl    237  N      0     Ph     0   OCOCH.sub.3                                           4-Me-1-                                           piperazinyl    238  N      0     Ph     1   4-pyr     N(Ph)(Me)    239  N      0     Ph     1   2-F-4-pyr N(Ph)(Me)    240  N      0     Ph     1   4-pym     N(Ph)(Me)    241  N      0     Ph     1   Ph        N(Ph)(Me)    242  N      0     Ph     0   OCOCH.sub.3                                           N(Ph)(Me)    243  N      0     Ph     1   2-F-4-pyr N(Me).sub.2    244  N      0     Ph     1   4-pym     N(Me).sub.2    245  N      0     Ph     1   4-pym     N(Me).sub.2    246  N      0     Ph     1   Ph        N(Me).sub.2    247  N      0     Ph     0   OCOCH.sub.3                                           N(Me).sub.2    248  N      0     Ph     1   4-pyr     N(Ph).sub.2    248  N      0     Ph     1   2-F-4-pyr N(Ph).sub.2    250  N      0     Ph     1   4-pym     N(Ph).sub.2    251  N      0     Ph     1   Ph        N(Ph).sub.2    252  N      0     Ph     0   OCOCH.sub.3                                           N(Ph).sub.2    ______________________________________

UTILITY SECTION

Biochemical Test Procedures

Neurotransmitter release assay.

The neurotransmitter release activities of the compounds in thisinvention were determined as reported in Drug Development Research, 19,285-300 (1990) and is a modification of the procedure described byMulder, et al., Brain Res., 70, 372 (1974). Both of these disclosuresare incorporated herein by reference. Male Wistar rats (Charles River)weighing 175-200 grams were used. The rats were housed for at leastseven days before the experiment in animal facility under 12/12 hourlight/dark cycle. Deionized water and standard rat chow (Purina) wereavailable ad libitum.

Rats were decapitated and brains were removed immediately. Slices (0.3mm thick) from the parietal cortex were prepared manually using arecessed Lucite guide. Slices were subsequently cut into 0.25×0.25 mmsquares with a McIlwain tissue chopper.

Cerebral cortical slices (approximately 100 mg wet weight) wereincubated in 10 ml Krebs-Ringer medium (KR) containing NaCl (116 mM),KCl (3 mM), CaCl (1.3 mM), MgCl₂ (1.2 mM), KH₂ PO₄ (1.2 mM), Na₂ SO₄(1.2 mM), NaHCO₃ (25 mM) and glucose (11.0 mM) to which 10 mCi ³H-choline (specific activity approximately 80 uCi/mM; DuPont-NEN) and 10nmol unlabeled choline had been added to give a final concentration of 1mM. The brain preparations were incubated for 30 minutes at 37° C. undera steady flow of 95% O2.5% CO₂. Under these conditions, part of theradioactive choline taken up by the preparation was converted intoradioactive acetylcholine (ACh) by the cholinergic nerve endings storedin synaptic vesicles, and released upon depolarization by high potassiumion (K⁺) containing media.

After labeling of the ACh stores, the slices were washed three timeswith non-radioactive KR medium and transferred to a superfusionapparatus to measure the drug effects on ACh release. The superfusionapparatus consisted of 10 thermostated glass columns of 5 diameters thatwere provided with GF/F glass fiber filters to support the slices(approximately 10 mg tissue/column). Superfusion was carried out inKR-medium (0.3 ml/min.) containing 10 mM hemicholinium-3 (HC-3). TheHC-3 prevents the reuptake of choline formed during the superfusion fromphospholipids and released ACh, which would be converted into unlabeledACh and released in preference to the pre-formed labeled ACh. The mediumwas delivered by a 25-channel peristaltic pump (Ismartec by Brinkman)and warmed to 37° C. in a thermostated stainless steel coil beforeentering the superfusion column. Each column was provided with a 4-wayslider value (Beckmann Instruments) which allowed rapid change of low tohigh K⁺ /KR-medium, and with two 10-channel 3-way values that were usedto change from drug-free to drug-containing low and high K⁺ /KR-medium.

After 15 min. of washout of non-specifically bound radioactivity,collection of 4 min. fractions was initiated. After three 4 min.collections, the original medium was changed to a KR-medium in which theKCl concentration has been increased to 25 mM (high K+-KR medium; S1).Depolarization-induced stimulation of release by high K+/KR-mediumlasted 4 min. Drug free low and high K+/KR-media were then substitutedby drug- and vehicle-containing low- and high-K+/KR medium, andsuperfusion was continued for three 4 min. collections with lowK+/KR-medium, one 4 min. collection with high K+/KR-medium (S2), and two4 min. collections with low-K+/Kr-medium.

Drug was added to the media by 100-fold dilutions of appropriateconcentrations of the drug (in 0.9% saline) with either low- orhigh-K+/KR-medium.

All superfusion fractions were collected in liquid scintillationcounting vials. After superfusion, the slices were removed from thesuperfusion columns and extracted with 1.0 ml of 0.1N HCl. Liquiscint(NEN) scintillation cocktail (12 ml) was added to superfusion fractionsand extracts, and the samples were counted in a Packard Tricarb LiquidScintillation Counter. No corrections were made for quenching.

The ratio of S2/S1 (as compared to controls where no drug was presentduring S2) was a measure of the ability of the drug to enhance ordepress stimulus-induced acetylcholine release. Per cent acetylcholine(ACh) enhanced release caused by 10 mM of drug using this assay areshown in Tables II-VII.

                  TABLE II    ______________________________________    Formula I where T = N(Ph)(Me)                                       mp,   % ACh Rel,    Ex   A       m      Q1   n    Q2   °C.                                             @ 10 uM    ______________________________________     5   CH      1      4-pyr                             1    4-pyr                                       184-6 178    12   CH      1      Ph   1    Ph   171-3 143    17   CH      0      Ph   1    2-F- 186-8 139                                  4-pyr    ______________________________________

                  TABLE III    ______________________________________     ##STR55##                                       mp,    % ACh Rel,    Ex   A      m     Q1   n   Q2      °C.                                              @ 10 uM    ______________________________________    1    CH     1     4-pyr                           1   4-pyr   200-3  169    7    CH     1     2-pyr                           1   2-pyr   157-9  125    8    CH     1     2-F- 1   2-F-4-pyr                                       198-203                                              233                      4-pyr    10   CH     1     Ph   1   Ph      178-80 182    13   CH     0     Ph   1   4-pyr   190-3  105    15   CH     0     Ph   1   2-F-4-pyr                                       170-2  84    18   CH     0     Ph   1   Ph      159-61 120    20   CH     1     4-pyr                           0   H       108-10 109    21   CH     1     4-pyr                           1   CO.sub.2 Et                                       168-70 161    22   CH     1     4-pyr                           0   OH      198-200    26   CH     1     2-pyr                           0   OH      168-70    27   CH     1     2-pyr                           0   OCOCH.sub.3                                       107-10    28   CH     1     4-pyr                           0   OCOCH.sub.3                                       178-80 129    30   N      0     H    0   H       231-5                                       (HCl                                       salt)    32   N      1     4-pyr                           1   4-pyr   196-8  228    33   N      0     Ph   0   SO.sub.2 Me                                       oil    34   N      0     Ph   0   H       oil    35   N      0     Ph   0   OH    ______________________________________

                  TABLE IV    ______________________________________     ##STR56##                                      mp,     % ACh Rel,    Ex  A      m     Q1   n   Q2      °C.                                              @ 10 uM    ______________________________________    2   CH     1     4-pyr                          1   4-pyr   140-43  192    11  CH     1     Ph   1   Ph       94-96  115    14  CH     0     Ph   1   4-pyr   128-31  134    16  CH     0     Ph   1   2-F-4-pyr                                      129-32  94    19  CH     0     Ph   1   Ph      114-16  126    23  CH     1     4-pyr                          0   H        83-6   135    24  CH     1     4-pyr                          1   CO.sub.2 Et                                      oil    25  CH     1     4-pyr                          0   OH      156-8    29  CH     1     4-pyr                          0   OCOCH.sub.3                                      139-40  214    31  N      0     H    0   H       180-5                                      (HCl salt)    ______________________________________

                  TABLE V    ______________________________________    Formula I where T = NMe.sub.2    ______________________________________                                       mp,   % ACh Rel,    Ex   A       m      Q1   n    Q2   °C.                                             @ 10 uM    ______________________________________    3    CH      1      4-pyr                             1    4-pyr                                       190-3 148    ______________________________________

                  TABLE VI    ______________________________________    Formula I where T = NPh.sub.2                                       mp,   % ACh Rel,    Ex   A      m     Q1     n   Q2    °C.                                             @ 10 uM    ______________________________________    4    CH     1     4-pyr  1   4-pyr 184-6 105    9    CH     1     2-F-4- 1   2-F-4-                                       179-80                                             106                      pyr        pyr    ______________________________________

                  TABLE VII    ______________________________________     ##STR57##                                      mp,    % ACh Rel,    Ex   A      m      Q1   n    Q2   °C.                                             @ 10 uM    ______________________________________    6    CH     1      4-pyr                            1    4-pyr                                      184-6  144                       HCl       HCl    ______________________________________

Utility

The foregoing test results suggest that the compounds of this inventionhave utility in the treatment of cognitive disorders and/or neurologicalfunction deficits and or mood and mental disturbances in patientssuffering from nervous system disorders like Alzheimer's Disease,Parkinson's Disease, senile dementia, multi-infarct dementia,Huntington's disease, mental retardation, Myasthenia Gravis, etc. Theabove-described in vitro assay is recognized as aiding in theidentification of drugs useful in the treatment of cognitive disordersand/or neurological function deficits and or mood and mentaldisturbances in patients suffering from nervous system disorders likeAlzheimer's Disease, Parkinson's Disease, senile dementia, multi-infarctdementia, Huntington's disease, mental retardation, Myasthenia Gravis,etc. Cook et al., Drug Development Research, 19, 301-304 (1990),Nickolson et al., Drug Development Research, 19, 285-300 (1990) andDeNoble et al., Pharmacology Biochemistry & Behavior, 36, 957-961(1990), all have shown via the above-described in vitro assay that thedrug DuP 996, which has the chemical name3,3-bis(4-pyridinylmethyl)-1-phenylindolin-2-one (linopirdine), isuseful in the treatment of cognition dysfunction.

DOSAGE FORMS

Compounds of this invention can be administered to treat saiddeficiencies by means that produces contact of the active agent with theagent's site of action in the body of a mammal. The compounds can beadministered by any conventional means available for use in conjunctionwith pharmaceuticals either as individual therapeutic agent or incombination of therapeutic agents. They can be administered alone, butare generally administered with a pharmaceutical carrier selected on thebasis of the chosen route of administration and standard pharmaceuticalpractice.

The dosage administered will vary depending on the use and known factorssuch as pharmacodynamic character of the particular agent, and its modeand route of administration; the recipient's age, weight, and health;nature and extent of symptoms; kind of concurrent treatment; frequencyof treatment; and desired effect. For use in the treatment of saiddiseases or conditions, the compounds of this invention can be orallyadministered daily at a dosage of the active ingredient of 0.002 to 200mg/kg of body weight. Ordinarily, a dose of 0.01 to 10 mg/kg in divideddoses one to four times a day, or in sustained release formulation waseffective in obtaining the desired pharmacological effect.

Dosage forms (compositions) suitable for administration contain fromabout 1 mg to about 100 mg of active ingredient per unit. In thesepharmaceutical compositions, the active ingredient will ordinarily bepresent in an amount of about 0.5 to 95% by weight based on the totalweight of the composition.

The active ingredient can be administered orally is solid dosage forms,such as capsules, tablets and powders; or in liquid forms such aselixirs, syrups, and/or suspensions. The compounds of this invention canalso be administered parenterally in sterile liquid dose formulations.

Gelatin capsules can be used to contain the active ingredient and asuitable carrier such as but not limited to lactose, starch, magnesiumstearate, steric acid, or cellulose derivatives. Similar diluents can beused to make compressed tablets. Both tablets and capsules can bemanufactured as sustained release products to provide for continuousrelease of medication over a period of time. Compressed tablets can besugar-coated or film-coated to mask any unpleasant taste, or used toprotect the active ingredients from the atmosphere, or to allowselective disintegration of the tablet in the gastrointestinal tract.

Liquid dose forms for oral administration can contain coloring offlavoring agents to increase patient acceptance.

In general, water, pharmaceutically acceptable oils, saline, aqueousdextrose (glucose), and related sugar solutions and glycols, such aspropylene glycol or polyethylene glycol, are suitable carriers forparenteral solutions. Solutions for parenteral administration preferablycontain a water soluble salt of the active ingredient, suitablestabilizing agents, and if necessary, butter substances. Antioxidizingagents, such as sodium bisulfite, sodium sulfite, or ascorbic acid,either alone or in combination, are suitable stabilizing agents. Alsoused are citric acid and its salts, and EDTA. In addition, parenteralsolutions can contain preservatives such as benzalkonium chloride,methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in "Remington'sPharmaceutical Sciences", A. Osol, a standard reference in the field.

Useful pharmaceutical dosage-forms for administration of the compoundsof this invention can be illustrated as follows:

Capsules

A large number of units capsules are prepared by filling standardtwo-piece hard gelatin capsules each with 100 mg of powdered activeingredient, 150 mg lactose, 50 mg cellulose, and 6 mg magnesiumstearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean,cottonseed oil, or olive oil is prepared and injected by means of apositive displacement was pumped into gelatin to form soft gelatincapsules containing 100 mg of the active ingredient. The capsules werewashed and dried.

Tablets

A large number of tablets are prepared by conventional procedures sothat the dosage unit was 100 mg active ingredient, 0.2 mg of colloidalsilicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystallinecellulose, 11 mg of starch, and 98.8 mg lactose. Appropriate coatingsmay be applied to increase palatability or delayed adsorption.

The compounds of this invention may also be used as reagents orstandards in the biochemical study of neurological function,dysfunction, and disease.

What is claimed is:
 1. A compound of formula: ##STR58## wherein: T isselected from the group:N(Ph)₂, N(Me)₂, N(Ph) (Me), ##STR59## wherein sis 1-3; and, A is selected from CH or N with the proviso that whan A isCH then T is not N(Ph)₂.
 2. A compound according to claim 1, wherein Ais CH.
 3. A compound according to claim 2, wherein T is N(Me)₂.
 4. Acompound according to claim 2, wherein T is N(Ph)(Me).
 5. A compoundaccording to claim 2, wherein T is ##STR60##
 6. A compound according toclaim 2, wherein T is ##STR61##
 7. A compound according to claim 2,wherein T is ##STR62##
 8. A compound according to claim 2, wherein T is##STR63##
 9. A compound according to claim 1, wherein A is N.
 10. Acompound according to claim 9, wherein T is N(Ph)₂.
 11. A compoundaccording to claim 9, wherein T is N(Me)₂.
 12. A compound according toclaim 9, wherein T is N(Ph)(Me).
 13. A compound according to claim 9,wherein T is ##STR64##
 14. A compound according to claim 9, wherein T is##STR65##
 15. A compound according to claim 9, wherein T is ##STR66##16. A compound according to claim 9, wherein T is ##STR67##